DESCRIPTION: Approximately 250,000 persons in the US have traumatic spinal cord injury (SCI), and at least another 400,000 individuals have spinal cord damage of non-traumatic etiologies. The longevity of those with SCI has increased over the decades because of effective treatments for urological and pulmonary complications. However, the SCI population is growing older and ever more costly to manage medically. Thus, it is increasingly imperative that we continue to understand the medical consequences of SCI and pursue safe and effective treatment options to minimize or prevent these adverse disorders. The mission of the CoE MCSCI is to improve quality of life and to increase longevity in individuals with SCI by identifying and intervening to reduce and/or prevent the secondary medical consequences of SCI, goals which are in the finest tradition of the VA's RR&D Service. The proposed Center of Excellence for the Medical Consequences of Spinal Cord Injury (CoE MCSCI) will continue to provide support for studies by investigators in several specialty areas of Medicine, Rehabilitation Medicine, Neurology, Neuropsychology, Epidemiology, Sleep Medicine, and Molecular Biology. The CoE physician/scientist-investigators will initiate interventional treatments for various medical complications, or strive o better characterize pathophysiological conditions. Therapeutic or investigational approaches that will be pursued include pharmacological and non-pharmacological interventions as follows: ibandronic acid to reduce bone loss in individuals with incomplete motor SCI who are ambulatory; a gut incretin [glucagon- like peptide (liraglutide)] to improve carbohydrate/lipid metabolism and soft tissue body composition; a novel adjunctive approach to improve routine bowel care by administering neostigmine and glycopyrrolate transdermally by iontophoresis; an oral vibrating capsule to improve bowel motility and evacuation; exoskeleton assisted walking (EAW) to improve colonic motility measured by SCI-QOL Bowel Management survey, radiopaque markers, and high resolution manometry; identification and classification of the degree of autonomic cardiovascular impairment; anti-hypotensive agents to raise blood pressure and prevent cognitive impairment [e.g., beta (3)-adrenoceptor agonist (mirabegron); an alpha agonist (midodrine), and a norepinephrine precursor (droxidopa)]; a novel meal with an enhanced ability for meal-induced thermogenesis to reduce risk of hypothermia upon cold exposure; paired central stimulation to strengthen existing neurological pathways to the hands; and home-based portable sleep monitoring compared to witnessed polysomnography for the identification of sleep disordered breathing. Compared to the general population, cardiovascular morbidity in persons with SCI occurs earlier in life and is more prevalent. Conventional risk factors for coronary artery disease may not accurately predict the presence of macrovascular disease. Thus, the measurement of emerging risk factors, as well as conventional risk factors, and the quantification of coronary artery calcium will continue to be studied in our CoE proposal to enable health professionals to better identify and treat persons with vascular disease. EAW in persons with SCI has proven to be a game-changing mechanical intervention for mobility and to improve several health- related conditions, including bowel dysfunction, which is proposed to be assessed in the CoE. A new molecular signaling pathway involving the de novo appearance of connexin hemichannels, may underlie muscle inflammation and atrophy after SCI and possibly other neurological disorders; inhibitors of these hemichannels may be proven to be potent therapeutic agents to reduce muscle atrophy after immobilization. The future holds exciting promise for innovative treatments to be incorporated into routine care associated with endocrine-metabolic, respiratory, gastrointestinal, autonomic, and musculoskeletal dysfunctions.